The experiments outlined in this proposal seek to locate a major gene underlying left-handedness in humans. Since handedness reflects the underlying cerebral cortical organization for language, as well as the lateralization of other higher cognitive and motor functions, understanding some of the molecular and developmental mechanisms that contribute to handedness is likely to provide insight into the development of cerebral hemispheric asymmetries and the specialization of cortical areas. The further relevance of this work to the development of cognitive abilities is emphasized by the association of handedness with a subtype of dyslexia in the group of families that we propose to study. Genetic linkage analysis will be applied to locate a major gene contributing to the left-handed phenotype in a unique group of Irish- American and Irish kindreds that are enriched for dyslexia and appear to share autosomal dominant transmission of left-handedness. The common geographic and ethnic origin from a small region of County Cork, Ireland, that is shared by these families is striking and may reflect a genetic founder effect. Candidate genes and chromosomal regions will be tested for linkage to left-handedness using polymorphic DNA markers in a subset of the affected (left-handed) individuals in the most informative families. If necessary, a whole genome screen will be conducted. First, a screen with polymorphic markers at 20 cM intervals will be initiated in a subset of the most informative individuals. Two- point linkage analysis will be conducted using the LINKAGE program. If any region attains a lod score >+2, finer flanking markers will be scored and multipoint linkage analysis will be conducted. Additional individuals will be genotyped and added to the analysis to increase power in the order of their families' predicted informativeness. If no linkage is found initially, finer markers will be scored, eventually leading to a 10 cM resolution autosomal genome screen. Linkage disequilibrium analysis will be conducted to attempt to narrow the chromosomal region to a few hundred kilobases or less. The distance between the closest flanking markers will be obtained using a combination of pulse-field gel electrophoresis (PFGE) and fluorescent in-situ hybridization (FISH). High resolution physical mapping and searching for expressed sequences within the plausible region will be pursued depending on the progress of the previous stages. Additionally, during the initial phases of the project, segregation analysis of handedness will be carried out using a subset of families followed at The Boston Children's Hospital with dyslexic probands. This work will contribute to our understanding of the development of cognitive functions and cerebral cortical structure. The study of these families offers an important opportunity, since no gene contributing to handedness or any aspect of cerebral lateralization has been identified in any vertebrate species.